Regulation of CD95/Fas signaling at the DISC

Abstract

CD95 (APO-1/Fas) is a member of the death receptor (DR) family. Stimulation of CD95 leads to induction of apoptotic and nonapoptotic signaling pathways. The formation of the CD95 death-inducing signaling complex (DISC) is the initial step of CD95 signaling. Activation of procaspase-8 at the DISC leads to the induction of DR-mediated apoptosis. The activation of procaspase-8 is blocked by cellular FLICE-inhibitory proteins (c-FLIP). This review is focused on the role in the CD95-mediated signaling of the death effector domain-containing proteins procaspase-8 and c-FLIP. We discuss how dynamic cross-talk between procaspase-8 and c-FLIP at the DISC regulates life/death decisions at CD95. Open QuestionsThe exact mechanism of CD95-mediated non-apoptotic signaling is not established. The stoichiometry of the CD95 DISC is a question of future studies. New molecules may be found to be associated with the DISC. CD95Signaling CD95 (also called APO-1; Fas; fas antigen; tumor necrosis factor receptor superfamily member 6, TNFRSF6) is a member of the DR family, a subfamily of the tumor necrosis factor receptor superfamily. 1 All members of the DR family are characterized by a cytoplasmic region termed death domain (DD). 2,3 DD are 80-100 amino-acid long motifs involved in the transduction of the apoptotic signal. Crosslinking of CD95 with its natural ligand (L), CD95L (CD178) 4 or with agonistic antibodies such as anti-APO-1 5 induces apoptosis in sensitive cells.Stimulation of CD95 has been also reported to trigger nonapoptotic pathways. [6][7][8][9][10][11][12] However, details of CD95-mediated non-apoptotic pathways remain largely unknown. Importantly, it has been shown that membrane-bound CD95L is essential for the cytotoxic activity, whereas soluble CD95L appears to promote autoimmunity and tumorigenesis via induction of non-apoptotic pathways, in particular NF-kB. 13 Future studies should elucidate more details on the mechanism of nonapoptotic action of CD95L.Binding of CD95L or agonistic antibodies to CD95 leads to formation of a receptor complex at the cellular membrane, which was named DISC. 14 The DISC consists of oligomerized receptors, the DD-containing adaptor molecule FADD/MORT1 (Fas-associated DD), procaspase-8 (FLICE, MACHa, Mch5), procaspase-10 and the c-FLIP (Figure 1). [15][16][17] The interactions between the molecules at the DISC are based on homotypic contacts. The DD of the receptor interacts with the DD of FADD, whereas the death effector domain (DED) of FADD interacts with the N-terminal tandem DEDs of procaspases-8, -10 and c-FLIP. As a result of DISC formation procaspase-8 is activated at the DISC resulting in the formation of the active caspase-8, which leads to apoptosis.The initial events of DISC formation have not been clarified yet. Pre-oligomerization of CD95 via the pre-ligand assembly domain has been reported to have an important role in apoptosis initiation. 18 Recently, there have been several new reports on the X-ray structure of the complex formed by isolated CD95 and FADD DDs. 19,20 ...

A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes

“…When death receptor Fas (CD95) interacts with its ligand FasL, the cytoplasmic tail of Fas recruits several proteins, including c-FLIP, the adaptor protein Fas-associated via death domain (FADD), and pro-caspase 8, which form a membrane-bound receptor complex referred to as the CD95 death-inducing signaling complex (DISC). 1 The homodimerization of pro-caspase 8 in the DISC leads to autocatalytic cleavage and the generation of active caspase 8, which in turn triggers the downstream activation of caspase 3 and eventually leads to apoptosis. 2 Two isoforms of c-FLIP protein have been identified in mice: the 24-kD c-FLIP R and the 55-kD c-FLIP L .…”

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

“…This pathway is initiated by interaction between the cell death receptor Fas (CD95/APO-1) and the Fas ligand (FasL/CD95L), which recruits caspase-8 (FLICE) to the death-inducing signalling complex (DISC) through interaction with the Fas-associated death domain adaptor protein. Cleaved (active) caspase-8 in turn activates downstream caspases, mainly caspase-3 [31]. Moreover, caspase-8 can indirectly activate caspase-9, the key enzyme in the cytochrome c (mitochondrial) apoptotic pathway, by its cleavage of BH3 interacting domain, which in turn evokes release of cytochrome c from mitochondria [32].…”

“…Moreover, caspase-8 can indirectly activate caspase-9, the key enzyme in the cytochrome c (mitochondrial) apoptotic pathway, by its cleavage of BH3 interacting domain, which in turn evokes release of cytochrome c from mitochondria [32]. The major endogenous regulator of Fas-mediated apoptosis is the cellular FLICE inhibitory protein (FLIP), which prevents cleavage of procaspase-8 and subsequent apoptotic signals by its recruitment and cleavage in the DISC instead of procaspase-8 [31].…”

The C-terminal Domain of the Long Form of Cellular FLICE-inhibitory Protein (c-FLIPL) Inhibits the Interaction of the Caspase 8 Prodomain with the Receptor-interacting Protein 1 (RIP1) Death Domain and Regulates Caspase 8-dependent Nuclear Factor κB (NF-κB) Activation

“…The DD is used to recruit adaptor proteins and is essential for the formation of a multiple-protein complex designated death-inducing signaling complex (DISC) (4). Upon engagement with Fas ligand (FasL), Fas recruits Fas-associated death domain (FADD), which contains a DD and a death effector domain (DED) via homotypic DD interaction in the DISC (5). Caspase 8 is an initiator caspase that contains two DEDs within its prodomain in addition to large and small protease subunits that facilitate recruitment to FADD (6,7).…”